Migraine is one of the most common neurological disorders, involving periodical attacks of headache and nausea as well as a plethora of other symptoms. Approximately 240 million people worldwide have an estimated 1.4 billion attacks of migraine each year (Tronvik, E. et al., JAMA, 1, 2003, pp. 65-69). Although considerable progress has been made, the pathophysiology of migraine is still not understood. It is a disorder that exhibits a spectrum of treatment responses in afflicted individuals. Although some of the patients can be cured with life style modification (trigger elimination) and can be treated with over-the-counter medications or by acupuncture, hypnosis and the like, the majority of the patients are in the need of prescription drugs for relief from the migraine and prevention of further attacks. The symptoms most in need of treatment are the head pain and gastrointestinal symptoms. But also photophobia and the aura have to be treated. The latter may also be quite disturbing and require treatment although its duration is relatively brief.
The exact pathogenesis of migraine is still unknown. In recent years a consensus has been emerging that in migraine both vascular and neural components are relevant and most probably interrelated.
Common drugs, which at present are used for the treatment of migraine and other forms of vascular headaches, are e.g. ergotamine, aspirin and NSAIDS. The gold standard of acute migraine treatment are the “triptans”, e.g. sumatriptan and zolmitriptan. These triptans elicit their antimigraine effects due to their vasoconstrictive properties and presumably their inhibition of the release of the neuropeptide calcitonin gene related peptide (CGRP).
A completely novel approach to treat migraine is the use of CGRP antagonists (Doods, H. et al., Br. J. Pharmacol., 129, 2000, pp. 420-423). Such CGRP antagonists have been disclosed, for example, in WO 98/11128. In WO 03/015787 a CGRP antagonist has been disclosed, namely 1-[N2-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxochinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine, which is, in combination with a 5-HT1B/1D agonist or an ergot alkaloid, especially useful for the prevention and/or treatment of migraine.
Recently, in WO 01/97807 angiotensin II (AT II) type I receptor antagonists have been disclosed for the prevention and/or therapeutic treatment of patients suffering from vascular headache conditions and more particularly migraine. These compounds are known to interfere with the renin-angiotensin system (RAS) and have been used so long to treat common cardiovascular diseases, particularly arterial hypertension and congestive heart failure.
Tronvik et al. disclosed results of a randomized, double blind, placebo-controlled crossover study with an angiotensin II (AT II) type I receptor antagonist (candesartan), of patients suffering from migraine. The authors concluded that candesartan provided effective migraine prophylaxis with a good tolerability profile (JAMA, 1, 2003, pp. 65-69).
Hansson et al. published results from a double-blind, placebo-controlled study with irbesartan of patients having mild/moderate hypertension. The use of an AT II type I receptor antagonist seems to be associated with a significant reduction in the incidence of headache commonly seen in hypertensive patients (Arch. Intern. Med. 160, 2000, pp. 1654-1658).
Etminan et al. published data of a meta-analysis of 27 studies involving 12110 patients treated for hypertension. The authors came to the conclusion that the risk of headaches was about one third lower in patients taking an AT II receptor antagonist than in those taking placebo (Am. J. Med. 112, 2002, pp. 642-646).